Rindom Buhl (soundpantry87)

An impressive clinical success has been observed in treating a variety of cancers using immunotherapy with programmed cell death-1 (PD-1) checkpoint blockade. However, limited response in most patients treated with anti-PD-1 antibodies remains a challenge, requiring better understanding of molecular mechanisms limiting immunotherapy. In colorectal cancer (CRC) resistant to immunotherapy, mismatch-repair-proficient or microsatellite instability-low (pMMR-MSI-L) tumors have low mutation burden and constitute ~85% of patients. Here, we show that inhibition of N6 -methyladenosine (m6 A) mRNA modification by depletion of methyltransferases, Mettl3 and Mettl14, enhanced response to anti-PD-1 treatment in pMMR-MSI-L CRC and melanoma. Mettl3- or Mettl14-deficient tumors increased cytotoxic tumor-infiltrating CD8+ T cells and elevated secretion of IFN-γ, Cxcl9, and Cxcl10 in tumor microenvironment in vivo. Mechanistically, Mettl3 or Mettl14 loss promoted IFN-γ-Stat1-Irf1 signaling through stabilizing the Stat1 and Irf1 mRNA via Ythdf2. buy Brensocatib Finally, we found a negative correlation between METTL3 or METTL14 and STAT1 in 59 patients with pMMR-MSI-L CRC tumors. Altogether, our findings uncover a new awareness of the function of RNA methylation in adaptive immunity and provide METTL3 and METTL14 as potential therapeutic targets in anticancer immunotherapy. Pediatric endoscopic pilonidal sinus treatment (PEPSiT) has become the new standard of care for pilonidal sinus disease (PSD) in pediatric patients. This study aimed to compare our current wound treatment protocol (laser epilation (LE) and oxygen-enriched oil-based gel dressing) with our previous protocol (silver sulfadiazine spray) and demonstrate its efficacy as means to prevent PSD recurrence in children undergoing PEPSiT. We retrospectively reviewed the data of 87 pediatric patients, 52 boys and 35 girls, with an average age of 17.1 years (range, 12-18) affected by chronic PSD, who underwent PEPSiT over a 24-month period (December 2017-December 2019). The patients were divided into two groups G1 (n = 47) treated with pre- and postoperative LE and oxygen-enriched oil-based gel dressing; and G2 (n = 40) treated with only postoperative dressing using silver sulfadiazine spray. The two groups were compared regarding the operative outcome, wound-healing time, disease recurrence, wound infections, and otherat our standardized pre- and postoperative wound management, including LE and oxygen-enriched oil-based gel dressing, was extremely safe and effective in reducing PSD recurrence and wound infection rate in pediatric patients undergoing PEPSiT. LE should be routinely offered as adjunctive treatment to all patients who receive PEPSiT and is strongly advocated to be started before surgery and continued after wound healing. More importantly, LE showed to have a role as a preventive modality in patients with recurrent folliculitis or infections at the intergluteal crease. It was also associated with significant improvement and acceleration of wound-healing time. LE and oxygen-enriched oil-based gel dressings were clinically safe and well-tolerated in all patients, with no adverse skin reactions or injuries to both therapies. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.Defining plant hydraulic traits is central to the quantification of ecohydrological processes ranging from land-atmosphere interactions, to tree mortality and water-carbon budgets. A key plant trait is the xylem specific hydraulic conductivity (Kx ), that describes the plant's vascular system capacity to transport water. While xylem's vessels and tracheids are dead upon maturity, the xylem is neither inert nor deadwood, various components of the sapwood and surrounding tissue remaining alive and functional. Moreover, the established definition of Kx assumes linear relations between water flux and pressure gradient by tacitly considering the xylem as a "passive conduit". Here, we re-examine thi